Human cancer vaccines

人类癌症疫苗

• 批准号: 12213116
• 负责人: SATO Noriyuki
• 金额: $ 32.19万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213116/
• 关键词: tumor antigens; peptide vaccines; CTL; clinical trials; autologous tumor; Bioinformatics; survivin; SYT-SSX; 癌ワクチン; 癌抗原ペプチド; 胃癌抗原遺伝子; 骨肉腫抗原遺伝子; HLA-A24; PBF; 肉腫; 臨床試験; 癌免疫; 癌抗原処理提示; 抗原ペプチド; hsc 70; 分子シャペロン; ヒト癌抗原; リカバリン; HLA-DR8

Three research projects were successfully studied. 1) We identified human osteosarcoma antigen PBF, papilloma-binding factor, from autologous CTL and osteosarcoma OS2000 line. PBF was expressed in a large part of soft part tumors as well as approximately 50 % tumors of epithelial origins, whereas it was not detected in normal part of tissues particularly in the protein level. These observations suggest that PBF could be utilized in the immunotherapy of cancers. 2) Reverse-immunological approaches of tumor antigens indicated that survivin could work as the tumor antigens. Particularly, survivin-derived 2Bpeptide induced CTL in many cancer patients in the HLA-A24 restricted manner. We are now underway the phase I clinical trials of this peptide in colon, breast, lung cancers, indicating that there are no adverse effects. Some of these patients demonstrated certain clinical responses such as reduction in tumor size in CT as well as in tumor marker levels. We are also underway the phase I clinical trials of HLA-A24-restricted B peptide derived from the SYT-SSX chromosomal translocation fusion product in synovial sarcoma patients. In this trial, there are no adverse effects, and two out of six patients indicated an increasing number of tetramer-positive CTL precursors. 3) We identified 35 novel tumor antigens by bioinformatics in silico approaches. Wet studies by using RT-PCR analysis confirmed that 7 out of 35 antigens have strict expression profiles as the tumor antigens.

三个研究项目都取得了成功。1)我们从自体CTL和骨肉瘤OS 2000细胞系中鉴定了人骨肉瘤抗原PBF，即乳头瘤结合因子。PBF在大部分软组织肿瘤以及约50%的上皮来源的肿瘤中表达，而在正常组织部分中未检测到，特别是在蛋白水平上。这些观察结果表明，PBF可用于癌症的免疫治疗。2)肿瘤抗原的反向免疫学研究表明，Survivin可以作为肿瘤抗原发挥作用。特别地，存活素衍生的2B肽在许多癌症患者中以HLA-A24限制性方式诱导CTL。我们现在正在进行这种肽在结肠癌、乳腺癌、肺癌中的I期临床试验，表明没有不良反应。其中一些患者表现出一定的临床反应，如CT中肿瘤大小以及肿瘤标志物水平降低。我们也正在进行来自SYT-SSX染色体易位融合产物的HLA-A24限制性B肽在滑膜肉瘤患者中的I期临床试验。在这项试验中，没有不良反应，六名患者中有两名表示四聚体阳性CTL前体的数量增加。3)我们通过计算机生物信息学方法鉴定了35种新的肿瘤抗原。通过RT-PCR分析的湿研究证实，35种抗原中有7种具有与肿瘤抗原相同的严格表达谱。

项目成果

Nabeta,Y.,Sahara,H.,Suzuki,K.,Wada,T.,Kikuchi,K.,Sato,N. et al.: "Induction of CTL from peripheral blood of HLA-A31 (+) gastric cancer patients by in vitro stimulation with antigenic peptide of signet ring cell carcinoma."Jap.J.Cancer. 91. 616-621 (2000)

锅田，Y.，撒哈拉，H.，铃木，K.，和田，T.，菊地，K.，佐藤，N.

Ida, K., Sato, N., et al.: "Improved induction of synovial sarcoma-reactive CTLs by SYT-SSX junction peptide/HLA-A*2402 complex anchor substitution."J.Immunol.. in press.

Ida, K.、Sato, N. 等人：“通过 SYT-SSX 连接肽/HLA-A*2402 复合物锚替代改善滑膜肉瘤反应性 CTL 的诱导。”J.Immunol.. 正在出版。

Takamura, Y., Ikeda, H., Sato, N., et al.: "Regulation of MHC class II expression in glioma cells by class II transactivator (C II TA)."Glia. 45. 392-405 (2004)

Takamura, Y.、Ikeda, H.、Sato, N. 等人：“II 类反式激活因子 (C II TA) 对神经胶质瘤细胞中 MHC II 类表达的调节”。

佐藤昇志,矢田純一,奥村康: "中外医学社"Annual Review免疫2000. 354 (2000)

Noboru Sato、Junichi Yada、Yasushi Okumura：“中外医学社”免疫学年度评论 2000. 354 (2000)

Shigehara,K.,Shujubo,N.,Ohmichi,M.,Abe,S.,Sato,N. et al.: "IL-12 and IL-18 are increased and stimulate IFN-γ production in sarcoid lungs."J.Immunol.. 166. 642-649 (2001)

Shigehara, K.、Shujubo, N.、Ohmichi, M.、Abe, S.、Sato, N. 等人：“IL-12 和 IL-18 增加并刺激结节肺中 IFN-γ 的产生。”J .免疫学.. 166. 642-649 (2001)